Abstract. 1/15 PMCID: PMC

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1 Prim Cre Compnion CNS Disord. 2012; 14(4): PCC.11m Published online 2012 Jul 5. doi: /PCC.11m01296 PMCID: PMC Eszopiclone Tretment for Insomni: Effect Size Comprisons in Ptients With Primry Insomni nd Insomni With Medicl nd Psychitric Comorbidity Andrew D. Krystl, MD, MS, W. Vughn McCll, MD, MS, Murizio Fv, MD, Hdine Joffe, MD, MSc, Cludio N. Sores, MD, PhD, Holly Hung, PhD, Todd Grinell, AB, Jcqueline Zummo, MPH, MBA, Willim Splding, MS, nd Rndll Mrshll, MD Deprtment of Psychitry nd Behviorl Sciences, Duke University School of Medicine, Durhm, North Crolin (Dr Krystl); Deprtment of Psychitry nd Behviorl Medicine, Wke Forest University Helth Sciences, Winston Slem, North Crolin (Dr McCll); Depression Clinicl nd Reserch Progrm, Deprtment of Psychitry, Msschusetts Generl Hospitl, Cmbridge (Dr Fv); Center for Women s Mentl Helth, Msschusetts Generl Hospitl, Boston (Dr Joffe); Deprtment of Psychitry nd Behviorl Neurosciences, McMster University, Toronto, Ontrio, Cnd (Dr Sores); nd Sunovion Phrmceuticls Inc, Mrlborough, Msschusetts (Drs Hung nd Mrshll, Ms Zummo, nd Messrs Grinell nd Splding) Corresponding uthor. Corresponding uthor: Andrew D. Krystl, MD, MS, DUMC 3309, Deprtment of Psychitry nd Behviorl Sciences, Duke University School of Medicine, Durhm, NC (Emil: krystl@phy.duke.edu). Received 2011 Sep 19; Accepted 2011 Dec 6. Copyright 2012, Physicins Postgrdute Press, Inc. Abstrct Objective: The purpose of this post hoc nlysis ws to compre the tretment effect size of eszopiclone 3 mg for insomni in ptients with dignosis of primry insomni nd in severl of the psychitric nd medicl conditions tht re most commonly comorbid with insomni. Method: Dt were nlyzed from 5 lrge, multicenter, rndomized, double blind, plcebo controlled studies of dult outptients of t lest 1 month durtion published between 2006 nd Diry derived indices of sleep nd dytime functioning nd the Insomni Severity Index were compred for ptients with primry insomni (DSM IV TR criteri, n = 828) nd for those with insomni comorbid with mjor depressive disorder (MDD, DSM IV TR criteri, n = 545), generlized nxiety disorder (GAD, DSM IV TR criteri, n = 595), perimenopuse/postmenopuse (Stges of Reproductive Aging Workshop criteri, n = 410), nd rheumtoid rthritis (Americn College of Rheumtology criteri, n = 153). Cohen d effect sizes were clculted for ech individul study s the between tretment difference score divided by the pooled stndrd devition. Results: Effect sizes rnged from 0.40 to 0.69 (smll medium) s erly s week 1 nd were mintined t t week 4 for sleep ltency, wke time fter sleep onset, nd totl sleep time. Sleep ltency nd totl sleep time effect sizes incresed from week 1 to week 4 in the primry insomni group. At week 4, effect sizes on ll 3 prmeters nd the Insomni Severity Index tended to be highest for the primry insomni ptients nd tended to be lowest for ptients with comorbid GAD nd MDD. The effect sizes for dytime functioning were smll for ll insomni ptient groups. Conclusions: Eszopiclone 3 mg is n effective tretment for insomni cross 5 cliniclly diverse ptient popultions; however, mgnitude of effect is medited by underlying comorbidity nd their tretments, with lrgest mesures of effect seen in primry insomni nd lowest in MDD nd GAD. These consistent results, nd the fct tht clinicl trils were conducted in ptients being treted s pproprite for their comorbid 1/15

2 clinicl conditions, support the results rel world generlizbility nd utility to clinicl prctice. Clinicl Points Eszopiclone 3 mg is n effective tretment for insomni cross 5 cliniclly diverse ptient popultions including those with primry insomni, mjor depressive disorder, generlized nxiety disorder, perimenopuse/postmenopuse, nd rheumtoid rthritis. For those with insomni nd mjor depressive disorder, eszopiclone ws studied in conjunction with concomitnt therpy with selective serotonin reuptke inhibitor, which ishow eszopiclone should be used in clinicl prctice in ptients with these insomni comorbidities. The prevlence of chronic insomni in the generl popultion rnges from s high s 22.1% using DSM IV 1 1 TR criteri to s low s 3.9% to 10.2% when dditionl ICD 10 or Reserch Dignostic Criteri re used. Ptients with insomni hve incresed rtes of medicl nd psychitric illness compred with the generl 2 popultion ; likewise, ptients with serious medicl nd psychitric disorders hve extremely high rtes of 3 6 7,8 insomni. For exmple, insomni is reported t rtes s high s 90% in depressed ptients, nd t lest two thirds of ptients with generlized nxiety disorder (GAD) hve 1 or more types of comorbid sleep 9,10 11,12 disturbnce. Mrkedly higher rtes of insomni re lso reported in ptients with pinful rthritis nd 13,14 in perimenopusl nd postmenopusl women. At the sme time, it hs been reported tht the ,18,19 incidence nd prevlence of mjor depressive disorder (MDD) or n nxiety disorder re higher in ptients dignosed with insomni. The consequences of insomni comorbidity re significnt. The presence of insomni in ptients with 20 primry medicl or psychitric dignosis is ssocited with reduced qulity of life, incresed functionl 8 impirment, nd higher illness relted symptom severity compred to ptients with similr medicl history nd no insomni. For exmple, high pin severity rtings hve been reported in ptients with insomni nd rthritis, nd high levels of resistnce to ntidepressnt tretment nd suicidl idetion hve been reported in ptients with insomni nd MDD. Insomni hs lso been found to be common residul 24 symptom nd significnt risk fctor for recurrence of MDD. Most medictions indicted for insomni re pproved on the bsis of double blind, plcebo controlled, rndomized clinicl trils in ptients with primry insomni (PI), excluding ptients with cliniclly significnt medicl or psychitric comorbidity. However, in most clinicl prctice settings, comorbidity is the rule rther 8,21,25 31 thn the exception. Unfortuntely, there re reltively few well designed rndomized clinicl trils tht hve evluted the more cliniclly relevnt questions of efficcy in ptients with comorbid insomni or reported dt on effect sizes to better estimte the clinicl effectiveness of tretment. Eszopiclone, γ minobutyric cid (GABA) ergic sedtive hypnotic, is thought to induce sleep vi llosteric modultion of GABA receptors enhncing inhibition of wke promoting brin regions. 32 A Eszopiclone hs been shown to significntly improve sleep onset nd mintennce in PI, 33,34 s well s in severl other psychitric 8,28 nd medicl popultions. 21,27 The pthophysiology of insomni in ech of these popultions is not known but my differ, 35 rising questions bout the reltive effectiveness of hypnotics to tret the comorbid insomni occurring in these different comorbid popultions. In ddition, insomni might be cused by medictions used to tret the comorbid conditions (eg, selective serotonin reuptke inhibitors [SSRIs] cusing ctivtion nd sleep frgmenttion). 36,37 The objective of this post hoc nlysis ws to compre the mgnitude nd pttern of the insomni response to 2/15

3 eszopiclone in PI nd cross severl of the most common insomni comorbidities in the presence of medictions codministered to tret those comorbid conditions. METHOD Dt were nlyzed seprtely from 5 lrge, multisite, rndomized, double blind, plcebo controlled studies published between 2006 nd 2009 of dult outptients of t lest 1 month durtion with the following: (1) PI 33 8 (DSM IV TR criteri, n = 828), (2) insomni comorbid with MDD (DSM IV TR criteri, n = 545), (3) 28 insomni comorbid with GAD (DSM IV TR criteri, n = 595), (4) insomni comorbid with rheumtoid rthritis (RA, n = 410), nd (5) insomni comorbid with perimenopuse/postmenopuse (PPM, n = 410). Detiled informtion on entry criteri, study design, smple chrcteristics, ptient disposition, nd efficcy 8,21,27,28,33 results ws previously reported in the primry publiction of ech tril. Key entry criteri for ech of the studies were s follows: (1) insomni: totl sleep time 6.5 hours t lest 3 times per week for the pst month nd sleep ltency > 30 minutes (PI study), 30 minutes (MDD, GAD, nd RA studies), nd 45 minutes (PPM study); (2) MDD: Hmilton Depression Rting Scle (HDRS) totl score 14 (the 17 item HDRS minus the 3 sleep disturbnce items); (3) GAD: Hmilton Anxiety Rting Scle totl score 20; (4) RA: Americn College of Rheumtology criteri nd tking stble dose of n RA mediction for dys prior to rndomiztion; nd (5) PPM stging: Stges of Reproductive Aging Workshop criteri. The onset of insomni ws required s n inclusion criterion to be temporlly relted to the comorbid MDD, RA, nd PPM in those 3 studies. For exmple, in the MDD study, onset of insomni must not hve predted onset of MDD by more thn 10 weeks; in the PPM tril, the menopusl trnsition must hve predted insomni onset, with no other secondry cuses of the insomni. No temporl reltionship ws required in those ptients with comorbid insomni nd GAD. Additionl study design chrcteristics re summrized in Tble 1. Assessments The following ptient self reported sleep prmeters were collected in the morning vi n interctive voice response system for the PI, MDD, RA, nd PPM trils nd vi electronic diry for the GAD tril: sleep ltency, defined s the number of minutes tken to fll sleep fter bedtime; wke time fter sleep onset, defined s the totl number of minutes of wke time fter initil sleep onset; nd totl sleep time, defined s the totl number of minutes of sleep during the night. Sleep qulity, dytime lertness, bility to concentrte, physicl well being, nd bility to function were lso evluted using individul 0 10 Likert scles, with higher scores indicting better qulity of sleep or functioning. Ptients lso completed the Insomni Severity Index 39 in order to ssess the overll severity of insomni. Sttisticl Methods The nlyses of ll efficcy endpoints were performed using the modified intent to tret popultion, consisting of ll ptients who were rndomized nd received t lest 1 dose of double blind study mediction. However, for the insomni comorbid with PPM nd insomni comorbid with RA studies, observed cses ws the unit of nlysis. Chnge from bseline to week 1 nd week 4 were nlyzed for ech of the subjective sleep nd dytime efficcy prmeters using n nlysis of covrince model, with tretment nd site s fixed effects nd bseline s the covrite. Vlues for wke time fter sleep onset nd sleep ltency were log trnsformed prior to the nlysis s in prior work. 8,21,27,28,33 Becuse number of key sleep prmeters re not normlly distributed in the generl popultion, 40 the medin of these vribles is more pproprite mesure of centrl tendency thn the men nd is therefore the centrl tendency sttistic reported. No djustment for multiple comprisons ws crried out since this ws n explortory post hoc comprison. Effect size clcultions from the PI, MDD, nd GAD studies were bsed on the lst observtion 3/15

4 crried forwrd method with chnge from bseline vlues, while effect size clcultions from the PPM nd RA studies were bsed on the completer nlysis with chnge from bseline vlues. These pproches were bsed on the prespecified nlysis method in the study protocols. Effect sizes bsed on Cohen d for ech individul study t week 1 nd week 4 re provided. The Cohen d effect size ws clculted for weekly efficcy mesures s the between tretment difference score divided by 41 the pooled stndrd devition. An effect size of 0.2 to < 0.5 nd 0.5 to < 0.8 hs been suggested to represent smll nd medium tretment effect, respectively, while n effect size 0.8 represents lrge 41 tretment effect. A timefrme of 4 weeks ws studied becuse the shortest of the studies included in this post hoc nlysis ws 4 weeks in durtion. RESULTS The bseline demogrphic nd clinicl insomni chrcteristics of ptients enrolled in the 5 trils re summrized in Tble 2. Between study differences were consistent with the comorbid dignosis. For exmple, ptients in the RA tril were the oldest (men ge of 52.1 yers), followed by the ptients in the PPM tril (49.1 yers), while the youngest ptients were those in the GAD nd MDD trils (men ge of 39.9 yers nd 41.0 yers, respectively). The mjority of ptients in ll 5 of the trils were women. The most notble between group difference ws greter overll insomni severity in the MDD ptients compred with those in the other studies, s shown by mrkedly higher sleep ltency nd wke time fter sleep onset, mrkedly shorter totl sleep time, nd higher Insomni Severity Index scores. Tretment with eszopiclone 3 mg ws ssocited with significnt reduction in sleep ltency nd wke time fter sleep onset nd increse in totl sleep time t week 4 in ll 5 trils (Figure 1A C). Across groups, the gretest reduction from bseline in sleep ltency nd wke time fter sleep onset nd gretest increse in totl sleep time ws observed in ptients with comorbid MDD. Following tretment with eszopiclone 3 mg, effect sizes clculted t week 1 were in the rnge (smll medium effect) for sleep ltency, wke time fter sleep onset, nd totl sleep time (Figure 2A B). Effect sizes t week 4 for sleep ltency, wke time fter sleep onset, nd totl sleep time were lso in the smll medium rnge ( ), but were somewht more divergent. Effect sizes for sleep ltency nd totl sleep time incresed further in the PI group from weeks 1 4 but tended to decrese from weeks 1 4 in the other trils. At week 4, effect sizes on ll mesures of sleep ltency, wke time fter sleep onset, totl sleep time, nd the Insomni Severity Index tended to be highest for the PI ptients nd tended to be lowest for ptients with comorbid GAD nd MDD (Tble 3). The effect sizes for dytime functioning (Likert rtings of dytime lertness, bility to concentrte, physicl well being, bility to function) were smll for ll insomni ptient groups (Tble 3). Figure 3A B shows the effect sizes for sleep qulity nd for dytime functioning for ech insomni group for weeks 1 nd 4. The effect sizes were consistently highest in the PI group nd tended to be lowest in ptients with comorbid GAD nd MDD. DISCUSSION Together, these studies provide findings tht re relevnt to substntil proportion of insomni sufferers treted by physicins. It is estimted tht only 25% of persons with insomni hve no ssocited comorbid condition, leving the mjority of ptients with ssocited psychitric nd medicl conditions tht contribute to sleep disturbnce in diverse wys. 35 To dte, however, there re no published epidemiologic studies reporting the specific prevlence of the mjor comorbid conditions observed within this popultion. Multiple studies hve found tht nxiety nd depressive disorders re the most common psychitric 4/15

5 comorbidities in ptients with chronic insomni. For exmple, 1 lrge study reported tht, mong persons with difficulty flling sleep, 37% hd n nxiety disorder nd 16.5% hd MDD. 42 Insomni is lso common complint in vriety of chronic somtic illnesses, including but not limited to chronic pin disorders such s bck pin, fibromylgi, osteorthritis, nd RA. In fct, lrge ntionl representtive helth survey (N = 49,000) in Norwy found tht pproximtely 25% of those with RA lso complin of insomni. 43 Endocrine disorders such s dibetes mellitus re lso commonly ssocited with insomni. In n epidemiologic study of over 3,200 primry cre ptients, 17% of those with insomni reported comorbid endocrine disorders. 44 Insomni complints re common during periods of life ssocited with somtic nd psychologicl discomforts such s menopusl trnsition. 45 Perimenopusl nd postmenopusl women typiclly hve more sleep complints thn younger women, 46 nd sleep problems re commonly seen in perimenopusl nd postmenopusl women, with prevlence rtes rnging from 15% to 60%. 13,47 The pthophysiology of chronic insomni is just beginning to be understood. To dte, substntil body of reserch into cusl models of insomni hs been conducted in ptients with PI, helthy norml volunteers, nd niml models. However, such studies re lcking for conditions wherein insomni is core symptom of other illnesses such s mood disorders, GAD, nd PPM. Hypnotics hve been used for decdes to tret insomni in wide rnge of ptients, regrdless of comorbid condition nd despite the fct tht the efficcy 52,53 nd tolerbility of these medictions were estblished only in ptients with PI. Our nlyses suggest tht eszopiclone is effective for the tretment of insomni cross 5 different ptient subgroups, with mixed smllto moderte effect sizes in ech of them. The level of improvement observed cross ll 5 conditions suggests tht even though the disrupted sleep seen in diverse conditions my not hve common pthophysiologic pthwy, ech cn be impcted to similr extent vi llosteric modultion of GABA A receptor inhibition of 32,54 wke promoting res, the presumed mechnism of ction of eszopiclone. Comprtive ssessments of the effects of other hypnotic gents cross insomni popultions re needed to determine the extent to which the similrities in improvement seen cross these insomni subgroups re unique to eszopiclone, common to ll gents tht enhnce GABA A receptor medited inhibition, or generl chrcteristic of phrmcologic promotion of sleep regrdless of mechnism of ction. Although the reltive effect size cross the 5 conditions vries somewht for the different insomni prmeters studied, there ppers to be somewht lrger effect size for PI, PPM, nd RA compred with MDD nd GAD. Also, in contrst to the PI group, the effect size on quntittive sleep prmeters in the MDD nd GAD groups ws somewht reduced by week 4. Differences between weeks 1 nd 4 could be relted to progressive improvement in the plcebo group over time, common phenomenon in centrl nervous system trils. Possible resons for the effect size nd pttern of response differences mong the comorbid popultions studied include the effects of the concomitnt medictions for the comorbid condition (eg, n SSRI) or physiologic differences between different subtypes of insomni in the vrious conditions. An effect of concomitnt medictions seems likely, given tht the 2 conditions for which n SSRI ws codministered with eszopiclone tended to hve the lowest effect sizes, nd tht SSRIs re known to improve insomni long with the totl syndrome in both MDD nd GAD. It is importnt to note tht, lthough the eszopiclone versus plcebo effect size ws found to be smller in MDD nd GAD compred with PI, PPM, nd RA, the bsolute degree of improvement in GAD nd MDD ptients from bseline with eszopiclone plus SSRI mediction ws s lrge or lrger thn the improvement seen in PI, PPM, nd RA ptients who received eszopiclone lone. As result, the degree of improvement seen in clinicl prctice (where no comprison with plcebo occurs) with eszopiclone in GAD nd MDD ptients, who re generlly treted with medictions such s SSRIs, would be expected to be t lest s lrge s the improvement seen in the other insomni subgroups. This is crucil point becuse studies crried out for US Food nd Drug Administrtion pprovl of hypnotic medictions re conducted in PI, lthough most ptients seen in clinicl prctice hve comorbid nxiety nd mood symptoms. It should therefore not be 5/15

6 concluded tht PI studies overestimte the results seen in clinicl prctice. There re severl importnt limittions to this study. Only 5 multicenter studies were vilble for inclusion in the nlysis, limiting the generlizbility of our conclusions. In the MDD study, both the bseline severity of insomni nd the degree of improvement were substntilly greter thn in the other conditions. Comprisons cross multiple types of ptient groups nd tril designs (eg, monotherpy versus combintion therpy) introduce considerble heterogeneity. This heterogeneity is prtly blnced by exmining the effect size of single mediction. The effect of eszopiclone lone in the MDD nd GAD popultions hs not been studied becuse of the ssumption tht pproprite tretment of insomni occurring with MDD nd GAD in clinicl prctice will lwys include n intervention trgeted to the MDD or GAD, long with insomni therpy. The effect size of eszopiclone lone on insomni in MDD nd GAD, nd the incrementl improvement in insomni occurring with eszopiclone bove nd beyond the effects of SSRI therpy, re of theoreticl/mechnistic interest becuse they illustrte both the limittions of typicl monotherpy for these conditions for insomni nd the extent to which the combintion of enhncing the inhibitory effects of GABA nd serotonin reuptke inhibition cn further benefit ptients. A further limittion is tht we did not evlute or ccount for the potentil influence of fctors such s ge, gender, bseline insomni severity, or other covrites of interest on the eszopiclone effect sizes. This limittion occurred becuse our priori pln ws to evlute effect size on the bsis of prespecified primry outcome nlysis for ech of the studies included. In summry, this effect size comprison showed reltively consistent effect of eszopiclone tretment of insomni cross 5 cliniclly diverse popultions. Moreover, ptients in these trils were lso being treted with pproprite clinicl therpies for their condition, including concomitnt tretment with SSRIs (GAD nd MDD), pproprite pin medictions (in RA), nd hormone supplementtion (perimenopuse), supporting the rel world generlizbility of the present study to clinicl prctice nd mitigting concerns tht rndomized clinicl trils conducted in restricted PI popultions for drug pprovl purposes do not show therpeutic responses representtive of those ttinble in typicl clinicl prctice. Drug nmes: escitloprm (Lexpro nd others), eszopiclone (Lunest), fluoxetine (Prozc nd others). Potentil conflicts of interest: Dr Krystl hs received grnt/reserch support from Abbott, Astells, Cephlon, Evotec, GlxoSmithKline, Merck, Ntionl Institutes of Helth, Neurocrine, Neurogen, Neuronetics, Pfizer, Phillips Respironics, Snofi Aventis, Somxon, Sunovion/Seprcor, Tked, nd Trnscept nd hs served s consultnt to Abbott, Actelion, Aren, Astells, AstrZenec, Axiom, Bristol Myers Squibb, Cephlon, Eisi, Eli Lilly, GlxoSmithKline, Jzz, Johnson & Johnson, King, Kingsdown Inc, Merck, Neurocrine, Neurogen, Neuronetics, Novrtis, Orgnon, Ortho McNeil Jnssen, Pfizer, Respironics, Roche, Snofi Aventis, Somxon, Somnus, Sunovion/Seprcor, Tked, nd Trnscept. Dr McCll hs served s consultnt to AstrZenec, Merck, Sely, nd Sunovion nd hs received honorri from Merck nd Sunovion. Dr Fv hs received reserch support from Abbott, Alkermes, Aspect Medicl Systems, AstrZenec, Bio Reserch, BrinCells, Bristol Myers Squibb, Cephlon, Clinicl Tril Solutions, Eli Lilly, Forest, Gneden Biotech, GlxoSmithKline, Johnson & Johnson, Lichtwer Phrm GmbH, Lorex, Ntionl Allince for Reserch on Schizophreni nd Depression, Ntionl Center for Complementry nd Alterntive Medicine, Ntionl Institute on Drug nd Alcohol Abuse, Ntionl Institute of Mentl Helth, Novrtis, Orgnon, Pmlb, Pfizer, Phrmvite, Roche, Snofi Aventis, Shire, Solvy, Synthelbo, nd Wyeth Ayerst; hs served on the dvisory bords of or s consultnt to Abbott, Amrin, Aspect Medicl Systems, AstrZenec, Auspex, Byer AG, Best Prctice Project Mngement, BioMrin, Biovil, BrinCells, Bristol Myers Squibb, Cephlon, Clinicl Trils Solutions, CNS Response, Compellis, Cypress, Dov, Eli Lilly, EPIX, Euthymics Bioscience, Fbre Krmer, Forest, GlxoSmithKline, Grunenthl GmbH, Jnssen, Jzz, Johnson & Johnson, Knoll, Lbophrm, Lorex, Lundbeck, MedAvnte, Merck, Methyltion Sciences, Neuronetics, Novrtis, Nutrition 21, Orgnon, Pmlb, Pfizer, PhrmStr, Phrmvite, Precision 6/15

7 Humn Biolbortory, PsychoGenics, Roche, Snofi Aventis, Seprcor, Schering Plough, Solvy, Somxon, Somerset, Synthelbo, Tked, Tetrgenex, Trnscept, TrnsForm, Vnd, nd Wyeth Ayerst; hs received speker nd publishing fees from Advnced Meeting Prtners, Americn Psychitric Assocition, AstrZenec, Belvoir, Boehringer Ingelheim, Bristol Myers Squibb, Cephlon, Eli Lilly, Forest, GlxoSmithKline, Imedex, Msschusetts Generl Hospitl Psychitry Acdemy/Primedi, Msschusetts Generl Hospitl Psychitry Acdemy/Reed Elsevier, Novrtis, Orgnon, Pfizer, PhrmStr, UBC Phrm, nd Wyeth Ayerst; is stock shreholder in Compellis; hs ptent pplictions for sequentil prllel comprison of design nd for combintion of zpirones nd bupropion in mjor depressive disorder; nd receives copyright roylties for the following Msschusetts Generl Hospitl ssessment tools: the Cognitive nd Physicl Functioning Questionnire, the Sexul Functioning Inventory, the Antidepressnt Tretment Response Questionnire, the Discontinution Emergent Sign nd Symptom scle, nd SAFER. Dr Joffe hs served s consultnt to Sunovion nd hs received grnt/reserch support from Byer, Forest, nd GlxoSmithKline. Dr Sores hs served s consultnt to AstrZenec, Bristol Myers Squibb, Lundbeck, nd Pfizer nd hs received grnt/reserch support from AstrZenec, Lundbeck, nd Pfizer. Drs Hung nd Mrshll, Ms Zummo, nd Messrs Grinell nd Splding re employees of Sunovion. Funding/support: The studies included in this post hoc nlysis were sponsored by Sunovion Phrmceuticls Inc, Mrlborough, Msschusetts. REFERENCES 1. Roth T, Coulouvrt C, Hjk G, et l. Prevlence nd perceived helth ssocited with insomni bsed on DSM IV TR; Interntionl Sttisticl Clssifiction of Diseses nd Relted Helth Problems, Tenth Revision; nd Reserch Dignostic Criteri/Interntionl Clssifiction of Sleep Disorders, Second Edition criteri: results from the Americ Insomni Survey. Biol Psychitry. 2011;69(6): [PubMed: ] 2. Ohyon MM. Prevlence of DSM IV dignostic criteri of insomni: distinguishing insomni relted to mentl disorders from sleep disorders. J Psychitr Res. 1997;31(3): [PubMed: ] 3. Thse ME. Correltes nd consequences of chronic insomni. Gen Hosp Psychitry. 2005;27(2): [PubMed: ] 4. Stner L. Comorbidity of insomni nd depression. Sleep Med Rev. 2010;14(1): [PubMed: ] 5. Bssetti CL. Nonmotor disturbnces in Prkinson s disese. Neurodegener Dis. 2011;8(3): [PubMed: ] 6. Louie GH, Tektonidou MG, Cbn Mrtinez AJ, et l. Sleep disturbnces in dults with rthritis: prevlence, meditors, nd subgroups t gretest risk: dt from the 2007 Ntionl Helth Interview Survey. Arthritis Cre Res (Hoboken) 2011;63(2): [PMCID: PMC ] [PubMed: ] 7. Thse ME. Antidepressnt tretment of the depressed ptient with insomni. J Clin Psychitry. 1999;60(suppl 17): discussion [PubMed: ] 8. Fv M, McCll WV, Krystl A, et l. Eszopiclone co dministered with fluoxetine in ptients with insomni coexisting with mjor depressive disorder. Biol Psychitry. 2006;59(11): [PubMed: ] 9. Ppdimitriou GN, Kerkhofs M, Kempeners C, et l. EEG sleep studies in ptients with generlized nxiety disorder. Psychitry Res. 1988;26(2): [PubMed: ] 7/15

8 10. Stein MB, Roy Byrne PP, Crske MG, et l. Functionl impct nd helth utility of nxiety disorders in primry cre outptients. Med Cre. 2005;43(12): [PubMed: ] 11. Drewes AM, Nielsen KD, Hnsen B, et l. A longitudinl study of clinicl symptoms nd sleep prmeters in rheumtoid rthritis. Rheumtology (Oxford) 2000;39(11): [PubMed: ] 12. Kirwn J, Heiberg T, Hewlett S, et l. Outcomes from the Ptient Perspective Workshop t OMERACT 6. J Rheumtol. 2003;30(4): [PubMed: ] 13. Dennerstein L, Dudley EC, Hopper JL, et l. A prospective popultion bsed study of menopusl symptoms. Obstet Gynecol. 2000;96(3): [PubMed: ] 14. Ohyon MM. Severe hot flshes re ssocited with chronic insomni. Arch Intern Med. 2006;166(12): [PubMed: ] 15. Tylor DJ, Lichstein KL, Durrence HH, et l. Epidemiology of insomni, depression, nd nxiety. Sleep. 2005;28(11): [PubMed: ] 16. Kneit Y, Ohid T, Uchiym M, et l. The reltionship between depression nd sleep disturbnces: Jpnese ntionwide generl popultion survey. J Clin Psychitry. 2006;67(2): [PubMed: ] 17. Ohyon MM, Hong SC. Prevlence of mjor depressive disorder in the generl popultion of South Kore. J Psychitr Res. 2006;40(1): [PubMed: ] 18. Ford DE, Kmerow DB. Epidemiologic study of sleep disturbnces nd psychitric disorders: n opportunity for prevention? JAMA. 1989;262(11): [PubMed: ] 19. Breslu N, Roth T, Rosenthl L, et l. Sleep disturbnce nd psychitric disorders: longitudinl epidemiologicl study of young dults. Biol Psychitry. 1996;39(6): [PubMed: ] 20. McCll WV, Reboussin BA, Cohen W. Subjective mesurement of insomni nd qulity of life in depressed inptients. J Sleep Res. 2000;9(1): [PubMed: ] 21. Roth T, Price JM, Amto DA, et l. The effect of eszopiclone in ptients with insomni nd coexisting rheumtoid rthritis: pilot study. Prim Cre Compnion J Clin Psychitry. 2009;11(6): [PMCID: PMC ] [PubMed: ] 22. Csper RC, Ktz MM, Bowden CL, et l. The pttern of physicl symptom chnges in mjor depressive disorder following tretment with mitriptyline or imiprmine. J Affect Disord. 1994;31(3): [PubMed: ] 23. McCll WV, Blocker JN, D Agostino R, Jr, et l. Insomni severity is n indictor of suicidl idetion during depression clinicl tril. Sleep Med. 2010;11(9): [PMCID: PMC ] [PubMed: ] 24. Nierenberg AA, Petersen TJ, Alpert JE. Prevention of relpse nd recurrence in depression: the role of long term phrmcotherpy nd psychotherpy. J Clin Psychitry. 2003;64(suppl 15): [PubMed: ] 25. Ferguson JM, Bielski RJ, Houston J, et l. Comprison of estzolm nd plcebo in the outptient tretment of insomni ssocited with mjor depression. Curr Ther Res Clin Exp. 1991;49(5): Joffe H, Petrillo L, Viguer A, et l. Eszopiclone improves insomni nd depressive nd nxious symptoms in perimenopusl nd postmenopusl women with hot flshes: rndomized, double blinded, plcebo controlled crossover tril. Am J Obstet Gynecol. 2010;202(2):171.e1 171.e /15

9 [PubMed: ] 27. Sores CN, Joffe H, Rubens R, et l. Eszopiclone in ptients with insomni during perimenopuse nd erly postmenopuse: rndomized controlled tril. Obstet Gynecol. 2006;108(6): [PubMed: ] 28. Pollck M, Kinrys G, Krystl A, et l. Eszopiclone codministered with escitloprm in ptients with insomni nd comorbid generlized nxiety disorder. Arch Gen Psychitry. 2008;65(5): [PubMed: ] 29. Fv M, Asnis GM, Shrivstv R, et l. Zolpidem extended relese improves sleep nd next dy symptoms in comorbid insomni nd generlized nxiety disorder. J Clin Psychophrmcol. 2009;29(3): [PubMed: ] 30. Asnis GM, Chkrburtty A, DuBoff EA, et l. Zolpidem for persistent insomni in SSRI treted depressed ptients. J Clin Psychitry. 1999;60(10): [PubMed: ] 31. Fv M, Asnis GM, Shrivstv RK, et l. Improved insomni symptoms nd sleep relted next dy functioning in ptients with comorbid mjor depressive disorder nd insomni following concomitnt zolpidem extended relese 12.5 mg nd escitloprm tretment: rndomized controlled tril. J Clin Psychitry. 2011;72(7): [PubMed: ] 32. Schrf M. Eszopiclone for the tretment of insomni. Expert Opin Phrmcother. 2006;7(3): [PubMed: ] 33. Wlsh JK, Krystl AD, Amto DA, et l. Nightly tretment of primry insomni with eszopiclone for six months: effect on sleep, qulity of life, nd work limittions. Sleep. 2007;30(8): [PMCID: PMC ] [PubMed: ] 34. Zmmit GK, McNbb LJ, Cron J, et l. Efficcy nd sfety of eszopiclone cross 6 weeks of tretment for primry insomni. Curr Med Res Opin. 2004;20(12): [PubMed: ] 35. Ktz DA, McHorney CA. Clinicl correltes of insomni in ptients with chronic illness. Arch Intern Med. 1998;158(10): [PubMed: ] 36. Feige B, Voderholzer U, Riemnn D, et l. Fluoxetine nd sleep EEG: effects of single dose, subchronic tretment, nd discontinution in helthy subjects. Neuropsychophrmcology. 2002;26(2): [PubMed: ] 37. Silvestri R, Pce Schott EF, Gersh T, et l. Effects of fluvoxmine nd proxetine on sleep structure in norml subjects: home bsed Nightcp evlution during drug dministrtion nd withdrwl. J Clin Psychitry. 2001;62(8): [PubMed: ] 38. Soules MR, Shermn S, Prrott E, et l. Executive summry: Stges of Reproductive Aging Workshop (STRAW) Climcteric. 2001;4(4): [PubMed: ] 39. Bstien CH, Vllières A, Morin CM. Vlidtion of the Insomni Severity Index s n outcome mesure for insomni reserch. Sleep Med. 2001;2(4): [PubMed: ] 40. Groeger JA, Zijlstr FR, Dijk DJ. Sleep quntity, sleep difficulties nd their perceived consequences in representtive smple of some 2000 British dults. J Sleep Res. 2004;13(4): [PubMed: ] 41. Cohen J. Sttisticl Power Anlysis for the Behviorl Sciences. 2nd ed. Hillsdle, NJ: Lwrence Erlbum; Roth T, Jeger S, Jin R, et l. Sleep problems, comorbid mentl disorders, nd role functioning in the 9/15

10 ntionl comorbidity survey repliction. Biol Psychitry. 2006;60(12): [PMCID: PMC ] [PubMed: ] 43. Sivertsen B, Krokstd S, Øverlnd S, et l. The epidemiology of insomni: ssocitions with physicl nd mentl helth: the HUNT 2 study. J Psychosom Res. 2009;67(2): [PubMed: ] 44. Terzno MG, Prrino L, Cirignott F, et l. Studio Morfeo Committee. Studio Morfeo: insomni in primry cre, survey conducted on the Itlin popultion. Sleep Med. 2004;5(1): [PubMed: ] 45. Budhirj R, Roth T, Hudgel DW, et l. Prevlence nd polysomnogrphic correltes of insomni comorbid with medicl disorders. Sleep. 2011;34(7): [PMCID: PMC ] [PubMed: ] 46. Young T, Rbgo D, Zgiersk A, et l. Objective nd subjective sleep qulity in premenopusl, perimenopusl, nd postmenopusl women in the Wisconsin Sleep Cohort Study. Sleep. 2003;26(6): [PubMed: ] 47. Shin C, Lee S, Lee T, et l. Prevlence of insomni nd its reltionship to menopusl sttus in middleged Koren women. Psychitry Clin Neurosci. 2005;59(4): [PubMed: ] 48. Poulin J, Chouinrd S, Pmpoulov T, et l. Sleep hbits in middle ged, non hospitlized men nd women with schizophreni: comprison with helthy controls. Psychitry Res. 2010;179(3): [PubMed: ] 49. Krystl AD, Ermn M, Zmmit GK, et l. ZOLONG Study Group. Long term efficcy nd sfety of zolpidem extended relese 12.5 mg, dministered 3 to 7 nights per week for 24 weeks, in ptients with chronic primry insomni: 6 month, rndomized, double blind, plcebo controlled, prllel group, multicenter study. Sleep. 2008;31(1): [PMCID: PMC ] [PubMed: ] 50. Xu M, Bélnger L, Ivers H, et l. Comprison of subjective nd objective sleep qulity in menopusl nd non menopusl women with insomni. Sleep Med. 2011;12(1): [PubMed: ] 51. Bourey RE. Primry menopusl insomni: definition, review, nd prcticl pproch. Endocr Prct. 2011;17(1): [PubMed: ] 52. Ntionl Institutes of Helth. Ntionl Institutes of Helth Stte of the Science Conference Sttement on Mnifesttions nd Mngement of Chronic Insomni in Adults, June 13 15, Sleep. 2005;28(9): [PubMed: ] 53. Schutte Rodin S, Broch L, Buysse D, et l. Clinicl guideline for the evlution nd mngement of chronic insomni in dults. J Clin Sleep Med. 2008;4(5): [PMCID: PMC ] [PubMed: ] 54. Lu J, Greco MA. Sleep circuitry nd the hypnotic mechnism of GABA A drugs. J Clin Sleep Med. 2006;2(2):S19 S26. [PubMed: ] Figures nd Tbles Tble 1. Chrcteristics of the 5 Clinicl Trils Included in the Current Anlysis Chrcteristic Primry Insomni Insomni + GAD Insomni + MDD Insomni + PPM Insomni + RA (Wlsh et l, (Pollck et l, 8 (Fv et l, 2006 ) (Sores et l, (Roth et l, /15

11 ) ) ) ) Study design Rndomized, Rndomized, Rndomized, Rndomized, Rndomized, double blind, double blind, double blind, double blind, double blind, plcebo controlled plcebo controlled plcebo controlled plcebo controlled plcebo controlled Inclusion criteri (sleep vribles) Open lbel tretment Double blind tretment, n Eszopiclone 3 mg Totl sleep time Totl sleep time 6.5 h Sleep ltency 6.5 h Sleep ltency > 30 min 30 min None Escitloprm 10 mg Totl sleep time 6.5 h Sleep ltency Totl sleep time 6.5 h Totl sleep time < 6.5 h 30 min Wke time fter sleep onset 45 min Sleep ltency 45 min Wke time fter sleep onset 45 min Fluoxetine 20 mg None (hormone None (stble RA replcement tretments therpy permitted) permitted) Plcebo Double blind tretment durtion 6 mo 8 wk 8 wk 4 wk 4 wk Primry outcome mesure Secondry outcome mesures (common to ll studies) Sleep ltency Sleep ltency Sleep ltency Sleep ltency Wke time fter sleep onset Wke time fter Wke time fter Wke time fter Wke time fter Wke time fter sleep onset, totl sleep onset, totl sleep onset, totl sleep onset, totl sleep onset, totl sleep time, sleep sleep time, sleep sleep time, sleep sleep time, sleep sleep time, sleep qulity, Likert qulity, Likert qulity, Likert qulity, Likert qulity, Likert scles, Insomni scles, Insomni scles, Insomni scles, Insomni scles, Insomni Severity Index Severity Index Severity Index Severity Index Severity Index Abbrevitions: GAD = generlized nxiety disorder, MDD = mjor depressive disorder, PPM = perimenopuse/postmenopuse, RA = rheumtoid rthritis. Tble 2. Bseline Demogrphic nd Ptient Chrcteristics of Ptients Enrolled in the 5 Trils Primry Insomni (Wlsh et l, ) Insomni + GAD (Pollck et l, ) Insomni + MDD Insomni + PPM Insomni + RA (R (Fv et l, ) (Sores et l, ) et l, ) Eszopiclone (n = 548) Plcebo (n = 280) Eszopiclone (n = 294) Plcebo (n = 299) Eszopiclone (n = 270) Plcebo (n = 275) Eszopiclone (n = 201) Plcebo (n = 209) Eszopiclone (n = 77) Plc (n = 76) 11/15

12 Age, men (SD), y 46.0 (11.8) 44.7 (11.8) (11.90) (11.64) 41.6 (10.7) 40.4 (11.3) 49.3 (4.1) 48.9 (3.9) 52.3 (8.1) 51 (9 Gender, n (%) Femle 336 (61.3) 169 (60.4) 194 (66.0) 198 (66.2) 180 (66.9) 182 (66.4) 201 (100) 209 (100) 71 (92.2) 6 (81 Mle 212 (38.7) 111 (39.6) 100 (34.0) 101 (33.8) 89 (33.1) 92 (33.6) (7.8) 1 (18 Rce, n (%) White 376 (68.6) 197 (70.4) 198 (67.3) 218 (72.9) 176 (65.4) 165 (60.2) 154 (77.4) 160 (76.9) 65 (84.4) 6 (82 Blck 88 (16.1) (15.6) (21.6) (13.6) 33 9 (11.7) 9 (1 (15.7) (13.7) (27.0) (15.9) Hispnic 6 (1.1) 6 (1.1) 29 (9.9) 21 (7.0) 30 (11.2) 21 (7.7) 16 (8.1) 15 (7.2) 2 (2.6) 3 (3 Asin 71 (13.0) (5.4) 15 (5.0) 3 (1.1) 9 (3.3) 1 (0.5) 0 1 (1.3) 1 (1 (11.1) Other 7 (1.3) 2 (0.7) 5 (1.7) 4 (1.3) 2 (0.7) 5 (1.8) 1 (0.5) Sleep ltency, medin, min Totl sleep time, medin, min Wke time fter sleep onset, medin, min Sleep qulity, 4.6 (1.6) 4.5 (1.5) 4.7 (1.6) 4.7 (1.5) 4.2 (1.7) 4.1 (1.8) 5.7 (1.7) 5.7 (1.7) 5.5 (1.7) 5 (1 men (SD) Dytime lertness, 5.1 (1.6) 5.0 (1.5) 5.0 (1.5) 5.0 (1.4) 4.6 (1.6) 4.4 (1.8) 6.3 (1.5) 6.3 (1.7) 6.1 (1.6) 6 (1 men (SD) Ability to concentrte, 5.7 (1.7) 5.5 (1.5) 5.2 (1.6) 5.1 (1.5) 4.7 (1.6) 4.6 (1.7) 6.7 (1.5) 6.7 (1.6) 6.7 (1.6) 6 (1 men (SD) Physicl 5.6 (1.7) (1.6) (1.6) (1.5) (1.5) 6 (1 well being, men (SD) (1.6) (1.4) (1.6) (1.6) Ability to function, men (SD) 5.9 (1.7) 5.7 (1.6) 5.3 (1.6) 5.2 (1.5) 4.9 (1.7) 4.8 (1.7) 6.9 (1.5) 7 (1.6) 6.6 (1.5) 6 (1 12/15

13 Insomni 419 (77.0) (75.0) (87.0) (52.8) (63.0) 3 Severity (80.4) (74.7) (90.1) (50.5) (56 Index, moderteto severe insomni, n (%) n = smple size rndomized t bseline. Abbrevitions: GAD = generlized nxiety disorder, MDD = mjor depressive disorder, PPM = perimenopuse/postmenopuse, RA = rheumtoid rthritis. Figure 1. Medin Chnge From Bseline to Week 4 in Ptients With Primry nd Comorbid Insomni Treted With Eszopiclone *P < **P =.001. ***P <.001. P <.01. P = Abbrevitions: GAD = generlized nxiety disorder, MDD = mjor depressive disorder, PPM = perimenopuse/postmenopuse, RA = rheumtoid rthritis. Tble 3. Tretment Effects on Sleep Ltency, Wke Time After Sleep Onset, nd Totl Sleep Time: Effect Sizes t Week 1 nd Week 4 Primry Insomni (Wlsh et l, Insomni + GAD (Pollck et l, Insomni + MDD (Fv et Insomni + PPM b (Sores et l, Insomni + RA b (Roth et l, /15

14 ) ) l, ) ) ) Vrible Week 1 Week 4 Week 1 Week 4 Week 1 Week 4 Week 1 Week 4 Week 1 Week 4 Sleep ltency Wke time fter sleep onset Totl sleep time Sleep qulity Dytime lertness Ability to concentrte Physicl wellbeing Ability to function Insomni Severity Index totl score c Effect size clcultions were bsed on the lst observtion crried forwrd method with chnge from bseline vlues. b Effect size clcultions were bsed on the completer nlysis with chnge from bseline vlues. c The Insomni Severity Index ws not ssessed t week 1. Abbrevitions: GAD = generlized nxiety disorder, MDD = mjor depressive disorder, PPM = perimenopuse/postmenopuse, RA = rheumtoid rthritis. Figure 2. Effect Sizes for Sleep Prmeters: Tretment of Primry nd Comorbid Insomni With Eszopiclone 14/15

15 Effect size (Cohen d): 0.2 to < 0.5 = smll tretment effect, 0.5 to < 0.8 = medium tretment effect, nd 0.8 = lrge tretment effect. Abbrevitions: GAD = generlized nxiety disorder, MDD = mjor depressive disorder, PPM = perimenopuse/postmenopuse, RA = rheumtoid rthritis. Figure 3. Effect Sizes for Sleep Qulity nd Dytime Effects: Tretment of Primry nd Comorbid Insomni With Eszopiclone Effect size (Cohen d): 0.2 to < 0.5 = smll tretment effect, 0.5 to < 0.8 = medium tretment effect, nd 0.8 = lrge tretment effect. Abbrevitions: GAD = generlized nxiety disorder, MDD = mjor depressive disorder, PPM = perimenopuse/postmenopuse, RA = rheumtoid rthritis. Articles from The Primry Cre Compnion for CNS Disorders re provided here courtesy of Physicins Postgrdute Press, Inc. 15/15